Biology subjects

Neill, J.

Publications and source records attributed to Neill, J..

6 recordsLinked to original sources

bioRxiv2026

Rate dependent Effects of AMPH on attentional processes as measured by 5C-CPT task

Background: ADHD is characterized by inattention and impulsivity. Stimulants such as amphetamine are the first line treatments for ADHD. Amphetamine (AMPH) works by increasing extracellular levels of dopamine and noradrenaline. Such stimulants are used to test predictive validity of animal tasks, where it has been reported that amphetamine improves rat 5-CSRTT accuracy when the session length is increased to 250 trials. This improvement in accuracy was observed later in the session as control performance declined. Proving that amphetamine can improve 5C-CPT task performance adds to the predictive validity of the task. No previous works has demonstrated the pro-attentional effects of amphetamine on sustained attention in rat 5C-CPT. We have previously shown that pharmacological manipulations of dopaminergic system improve waiting impulsivity in a rate dependent manner and the importance of analysing the data using Oldham method. The present study extends this work to investigate the effect of amphetamine on attentional processes. Objective: to investigate effects of amphetamine on attentional processes as measured by 5C-CPT task using correlational analysis and group performance. Methods: Trained female Lister hooded rats were tested with AMPH (0.1, 0.2 and 0.4 mg/kg) under reduced stimulus duration schedule (0.25,0.5,1,1.5 and 2s SD) over normal length session (120 trials). Correlational analysis (Oldham method) was used to understand the relationship between baseline performance measures and the change following administration of AMPH. Results: The highest dose of AMPH impaired attentional performance in the 5C-CPT under reduced SD challenge (0.5s,1s,1.5s and 2s). This impairment was due to increase in FAR. Previous studies in 5-CSRTT suggest that reducing the SD increases attentional demand in the form of reducing accuracy without affecting waiting impulsivity. However, the 5-CSRTT does not include non-target trials, therefore, it cannot be used to measure sustained attention (SI) and responsivity index. The 5C-CPT requires greater attentional resources than the 5-CSRTT.This study is the first to report that reducing the SD changes responsivity index (bias) rather than measures of sustained attention (sensitivity index) in the 5C-CPT. Control sensitivity index did not change until the SD was reduced to less than 0.5s and this change was due to a change in baseline responsivity index (bias). Performance under each reduced SD revealed that the highest dose of AMPH (0.4 mg/kg) showed a tendency toward reducing sensitivity index at 0.5, 1.0 and 1.5s SDs. Under 1.0s SD, the highest dose of AMPH changed sustained attention (SI, HR and FAR) and omission in a rate-dependent manner without changing responsivity index. Performance across the session revealed that the impairment in sustained attention was observed at the beginning of the session. In the third trial block, Oldham method revealed an inverse relationship between baseline accuracy and the change following administration of 0.2 mg/kg AMPH, indicative of a rate-dependent effect. Conclusions: This study successfully demonstrates rate-dependent effects of AMPH on measures of attentional performance in the 5C-CPT. This experiment also demonstrates that responsivity index is sensitive to reduced SD challenge. To our knowledge this is the first study to report the presence of a direct relationship between baseline sustained attention and magnitude of improvement following administration of 0.4 mg/kg AMPH and an inverse relationship between baseline accuracy and the change following administration of 0.2 mg/kg AMPH in 5C-CPT task. Future studies should test lower doses of amphetamine (0.05 and 0.1 mg/kg) over extended session length (250 trials) to reveal the pro-attentional effects of this drug on 5C-CPT performance measures.

animal behavior and cognition↗

bioRxiv2026

Stromal state plasticity defines risk and therapeutic opportunity in recalcitrant inflammatory bowel disease

Inflammatory bowel diseases (IBD) remain a relapsing, treatment-refractory disorder marked by progressive tissue injury and inflammation despite expanding immune-targeted therapies. We established a prospective cohort integrating stromal biobanking, functional phenotyping, cross-cohort benchmarking, and outcome modeling to define disease-anchored cellular states. Colonic myofibroblasts from 34 individuals spanning health, ulcerative colitis, and Crohns disease resolved into two dominant states: inflammatory (IMFs) and quiescent (QMFs) myofibroblasts. QMF predominance forecasted remission, whereas IMF predominance increased the odds of worsening endoscopic severity despite therapy escalation during follow-up by [~]4.6-fold, linking early stromal biology to clinical outcomes. Unlike QMFs, IMFs exhibited a senescence-associated secretory phenotype that impaired epithelial stemness, barrier integrity, and innate immune fitness. State-guided prioritization identified EDNRB-antagonism as a high-confidence stromal intervention, reversing pathogenic phenotypes across orthogonal assays and species. Outcome simulation positioned stromal-state reversibility by EDNRB-antagonism as a precision axis, reducing odds of recalcitrance by [~]96.4% and reframing treatment resistance as a reversible stromal state. Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=185 HEIGHT=200 SRC="FIGDIR/small/720931v2_ufig1.gif" ALT="Figure 1"> View larger version (88K): org.highwire.dtl.DTLVardef@3b2c50org.highwire.dtl.DTLVardef@da5400org.highwire.dtl.DTLVardef@1c100c1org.highwire.dtl.DTLVardef@1882e1_HPS_FORMAT_FIGEXP M_FIG C_FIG In this work, Tindle et al. identify reversible stromal states that govern remission vs. recalcitrant outcomes in IBD and nominate precision reprogramming of pathogenic myofibroblasts as a new therapeutic strategy.

physiology↗

bioRxiv2025

Too little and too much: balanced hippocampal, but not medial prefrontal, neural activity is required for intact novel object recognition in rats

Impaired GABAergic inhibition, so-called neural disinhibition, in the prefrontal cortex and hippocampus has been linked to cognitive deficits. The novel object recognition (NOR) task has been used widely to study cognitive deficits in rodents. However, the contribution of prefrontal cortex and hippocampal GABAergic inhibition to NOR task performance has not been established. Here, we investigated NOR task performance in male Lister Hooded rats following regional neural disinhibition or functional inhibition, using intra-cerebral microinfusion of the GABA-A receptor antagonist picrotoxin or agonist muscimol, respectively. Our infusion targets were the medial prefrontal cortex (mPFC), dorsal hippocampus and ventral hippocampus. Using a within-subjects design, we compared NOR task performance (1-min retention delay) following bilateral regional saline, picrotoxin or muscimol infusions made before the acquisition phase. In mPFC, neither functional inhibition nor neural disinhibition affected object recognition memory. However, in both dorsal and ventral hippocampus, neural disinhibition impaired NOR relative to saline control, mainly by reducing novel object exploration time. In addition, functional inhibition of dorsal hippocampus impaired NOR, whereas ventral hippocampal functional inhibition tended to reduce novel object exploration at the highest dose used (alongside substantial non-specific behavioural effects). Overall, our data suggest that hippocampal, but not prefrontal, GABAergic inhibition contributes to NOR at a 1-min retention delay. Moreover, such NOR performance likely requires balanced neural activity in the dorsal hippocampus, with both too little and too much dorsal hippocampal activity impairing NOR memory. Our findings support that the NOR task can be used to investigate hippocampal GABAergic dysfunction in rodent models. Significance statementImpaired GABAergic neural inhibition in the prefrontal cortex and hippocampus has emerged as a key neuropathological feature of cognitive disorders. The novel object recognition (NOR) task is used widely in rodent models to investigate cognitive impairments relevant to cognitive disorders. However, the role of hippocampal and prefrontal GABAergic inhibition in NOR is unclear, limiting interpretations as to how NOR deficits in rodent models may relate to this key pathological feature of many cognitive disorders. Here, we show that impaired hippocampal GABAergic inhibition impairs NOR in rats, whereas prefrontal GABAergic inhibition is not required. Thus, the NOR task may be used to investigate hippocampal GABAergic dysfunction in rodent models.

neuroscience↗

bioRxiv2023

Rate dependent effects of SKF 38393 and amphetamine on waiting impulsivity in the 5C-CPT

RationaleStimulants are the first-line treatment for attention-deficit/hyperactivity disorder (ADHD). However, the ensuing risk of abuse with stimulants means there is an urgent need for new, low-risk therapeutic agents. D1 receptors play an important role in the cognitive enhancing effects of stimulants and thus may provide a therapeutic target. Previous pre-clinical studies have shown that selective activation of D1 receptors improves sustained attention in the 5C-CPT without improving waiting impulsivity (premature response). ObjectiveThe aim of the present experiment was to compare the effects of the selective D1 receptor agonist SKF 38393 to a standard ADHD treatment (amphetamine) on waiting impulsivity in the 5C-CPT under extended inter-trial intervals. Oldhams method was used to determine the presence of a rate-dependent effect. MethodsAdult female Lister hooded rats were trained to criterion in the 5C-CPT (>70% accuracy, < 30% omission and < 40% false alarms). Effects of the selective D1 receptor agonist SKF 38393 (2-6 mg/kg) or amphetamine (0.1-0.4 mg/kg) were investigated under behavioural manipulations to challenge inhibitory response control. ResultsThe highest dose of SKF 38393 and the two highest doses of amphetamine improved waiting impulsivity in a baseline dependent manner. The clockwise movement of the regression line indicates that, as the dose increases, the magnitude of improvement increases in a manner consistent with baseline performance. ConclusionsThese findings support further clinical investigation of D1 receptor modulators to facilitate the discovery of improved medications for impulsive behaviour related disorders such as ADHD. The concept of rate dependency applies to effects of SKF 38393 or amphetamine on waiting impulsivity. Oldhams correlation method may present an opportunity to enhance the translational value of research in the preclinical laboratory to the clinic.

animal behavior and cognition↗

bioRxiv2023

The dopamine inhibitor GBR12909 improves attention and compulsive behaviour in female rats

BackgroundStimulants such as methylphenidate are the first-line treatment for attention deficit hyperactivity disorder (ADHD). A principal mechanism of action for these drugs is to reduce dopamine reuptake in the striatum. However, the ensuing risk of abuse with such stimulants means there is an urgent need for new, low-risk therapeutic agents. GBR12909 is a highly selective dopamine reuptake inhibitor, making it an important experimental tool. Indeed, this drug completed Phase II clinical trials for treatment of cocaine abuse. Understanding such drugs has the potential to expand our understanding of the striatal dopamine contribution to impulsivity, attention and compulsive behaviour and will help the development of novel targeted treatments for ADHD without an abuse risk. AimsThe aim of this work was to examine the role of low doses of GBR12909 on attention, impulsivity and compulsive behaviour as measured by 5C-CPT. Oldhams methods was used to determine the presence of a rate-dependent effect. MethodsFemale Lister hooded rats were trained to criterion in the 5C-CPT (>70% accuracy, < 30% omission and < 40% false alarms). Effects of GBR12909 (0.25-1 mg/kg) were investigated on attention, impulsivity and compulsive behaviour under challenging task conditions. ResultsThe two lowest doses of GBR12909 improved selective attention in a rate-dependent manner while the highest dose of GBR 12909 showed a tendency toward improving compulsive behaviour in a baseline-dependent manner. However, GBR 12909 impaired waiting impulsivity in a baseline-dependent manner. ConclusionsGBR12909 has a clearly beneficial effect on attention and compulsive behaviour in the female rat. These findings support further clinical investigation of GBR-type dopamine uptake blockers or GBR analogues to facilitate the discovery of medications for inattentive ADHD, stimulant abuse, compulsive drug seeking behaviour and obsessive-compulsive disorder.

animal behavior and cognition↗

bioRxiv2021

Twenty-one Year Trends for Shorebirds, Waterfowl, and Other Waterbirds at Great Salt Lake, Utah

Millions of wetland-dependent birds annually depend on saline lakes and associated wetlands in the western United States. Understanding the population status and trends of birds with different life histories and habitats can guide efforts to secure water resources needed to sustain bird habitats. We used a 21-year dataset to examine population trends for 24 survey units presumed to be high-quality habitat for migratory shorebirds, waterfowl, and other waterbirds at Great Salt Lake and associated wetlands. As expected for high-quality habitats, we found stable or positive trends for 36 of 37 species or groups in fall, spring, or both seasons when considering survey units in aggregate. Despite stable or positive aggregate trends, negative trends did occur in some individual survey units. Foraging, migration distance, and taxonomic groupings were unrelated to trend direction. Research is needed to test whether survey units represent high-quality habitat. With declining regional water resources, stable and positive aggregate trends reinforce the importance of surveyed units at Great Salt Lake and associated wetlands to wetland-dependent birds. Ensuring continuation of stable and positive trends will require identifying environmental factors - including water quantity and quality - driving trends, and require coordinated regional management and monitoring of wetland-dependent birds.

ecology↗